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Biomedical subjects

M R Spitz

Publications and source records attributed to M R Spitz.

At least 37 records · Page 2Linked to original sources
PubMed2001

Molecular epidemiologic studies within the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

OBJECTIVE: To conduct timely epidemiologic investigations of molecular/genetic markers that may contribute to the development of prostate, lung, colorectal, or other cancers within the Selenium and Vitamin E Cancer Prevention Trial (SELECT), and to evaluate interactions between these markers and the study interventions. METHODS: The epidemiologic studies within SELECT will be based on 32,400 men aged 55 years or older (age 50 or older for the African-American men) enrolled into an intergroup, randomized, placebo-controlled, double-blind, phase III prevention trial of supplemental selenium and vitamin E developed and funded by the National Cancer Institute, and coordinated by the Southwest Oncology Group. During the 12-year study period approximately 1500-2000 cases of prostate cancer, 800 lung cancers, and 500 colon cancers are estimated to be diagnosed, based on data from the ongoing Prostate Cancer Prevention Trial of finasteride. A modified fasting blood sample will be processed to collect plasma for analysis of micronutrients, hormones, cytokines, and other proteins. Buffy-coat derived white blood cells collected at baseline will be used for isolation of DNA and establishment of immortalized cell lines. Red blood cells will be stored for analysis of hemoglobin adducts and other components. RESULTS: Specific results anticipated from these molecular studies will provide information on factors hypothesized to contribute to prostate cancer risk and that may modify the efficacy of either trial supplement, including: steroid sex hormones and several polymorphic genes that encode proteins affecting androgenic stimulation of the prostate, including the androgen receptor, steroid 5alpha-reductase type II, CYP17, and beta-hydroxysteroid dehydrogenase; polymorphisms of DNA repair genes and carcinogen metabolism genes, including those involved in the activation of chemical carcinogens to reactive intermediates (e.g., CYP1A1) or the detoxification of reactive intermediates (e.g., glutathione S-transferase M1); DNA and protein adducts; and insulin-like growth factors and leptin. CONCLUSION: SELECT offers an excellent opportunity to conduct molecular epidemiologic investigations to assess gene-environment interactions and their role in prostate, lung, and colon carcinogenesis.

Colorectal Neoplasms↗
PubMed2001

Polymorphic hCHK2/hCds1 codon 84 allele and risk of squamous cell carcinoma of the head and neck--a case-control analysis.

Checkpoint kinase 2 (hCHK2/hCds1) is a tumor suppressor gene involved in cell-cycle control. A hCHK2/hCds1 polymorphism in codon 84 (A-->G at nucleotide 252) was recently identified in Li-Fraumeni syndrome patients. Because cell cycle regulates DNA repair that is associated with cancer risk, we hypothesized that this new polymorphism exists in the general population and is associated with cancer risk. To test this hypothesis, we evaluated the role of this polymorphism in a case-control study of 215 non-Hispanic white patients with newly diagnosed squamous cell carcinoma of the head and neck (SCCHN) and 229 frequency-matched cancer-free controls. We found that the hCHK2/hCds1 codon 84 variant was rare and less frequent in non-Hispanic white cases (0.0186) than in controls (0.0437; P = 0.033). Although no variant homozygotes were detected in these cases and controls, heterozygosity protected against SCCHN, representing a 60% reduction of risk (adjusted odds ratio = 0.40; 95% confidence intervals, 0.17-0.93) compared with wild-type homozygotes. The variant allele was also rare in other ethnic groups (0.0487, 0.0095 and 0.0541 in 115 African Americans, 105 Hispanic Americans and 111 native Chinese, respectively), and only one variant homozygous individual (a Chinese subject) was identified. These results suggest that this hCHK2/hCds1 codon 84 polymorphism is rare and may have a protective role in the aetiology of SCCHN in non-Hispanic whites. Larger studies are warranted to confirm this finding and further mechanistic studies are needed to understand biological relevance of this polymorphism.

Aged↗
PubMed2001

The association of microsomal epoxide hydrolase polymorphisms and lung cancer risk in African-Americans and Mexican-Americans.

This study evaluated the influence of genetic polymorphisms in the microsomal epoxide hydrolase (mEPHX) gene on lung cancer risk in a case-control study of two different ethnic groups, Mexican-Americans and African-Americans. There were 138 lung cancer cases (60 Mexican-American and 78 African-American) and 148 controls (76 Mexican-American and 72 African-American). There was a significant difference in the distribution of the mEPHX exon 4 polymorphism between the two ethnic groups with African-Americans more likely to be heterozygous and Mexican-Americans to be wild-type. There was no significant difference between the ethnic groups for the allelic distribution of the mEPHX exon 3 polymorphism. When the exon 4 and exon 3 polymorphism distributions in cases and controls were examined by ethnicity, only the Mexican-American cases showed a substantial proportion with the exon 4 polymorphism. The exon 4 polymorphism was associated with a significantly increased risk of lung cancer only among the Mexican-American cases (adjusted OR 3.6, 95% CI 1.26, 10.42). Younger Mexican-Americans with the exon 4 polymorphism had a greater risk of lung cancer than older members of their groups (adjusted OR 7.4, 95% CI 1.36, 40.23; 1.6, 95% CI 0.33, 7.80, respectively). The exon 3 polymorphism did not appear to significantly increase the risk of lung cancer in all but one study group examined. Mexican-Americans younger than 65 years did demonstrate an elevated risk of lung cancer (adjusted OR 4.6, 95% CI 1.19, 17.56). However, no statistically significant risk was observed in the African-American study groups for both exon 3 and exon 4 polymorphisms. These findings suggest that the presence of the exon 4 and exon 3 polymorphisms of mEPHX may be associated with an increased risk of lung cancer particularly among younger Mexican-Americans in this study.

Aged↗
PubMed2001

Cyclin D1 polymorphism and risk for squamous cell carcinoma of the head and neck: a case-control study.

A G-->A polymorphism (G870A) in exon 4 of the cyclin D1 (CCND1) gene creates an alternative splice site in its mRNA, encoding a protein with an altered C-terminal domain. It has been suggested that DNA damage in cells with the A allele bypasses the G(1)/S checkpoint of the cell cycle more easily than damage in cells without the A allele. Because CCND1 plays a critical role in cell cycle control and reduced DNA repair capacity is associated with an increased risk for squamous cell carcinoma of the head and neck (SCCHN), we hypothesize that this CCND1 polymorphism modulates individual susceptibility to SCCHN. To test this hypothesis we evaluated the frequency of the polymorphism in a hospital-based case-control study of 233 newly diagnosed SCCHN patients and 248 non-cancer controls. The cases and controls were frequency matched by age (+/-5 years), sex and tobacco use. All subjects were non-Hispanic whites. We found that the A allele frequency was slightly higher in the cases (0.485) than in the controls (0.425), but the difference was borderline statistically significant (P = 0.064). The frequencies of the CCND1 AA, GA and GG genotypes were 23.6, 49.8 and 26.6%, respectively, in cases and 16.5, 52.5 and 31.5%, respectively, in controls. Multivariate logistic regression analysis adjusting for age (in years), sex, smoking and alcohol use was performed to calculate odds ratios (OR) and 95% confidence intervals (CI). Compared with the wild-type CCND1 GG, the CCND1 A G genotype was associated with a non-significantly increased risk (adjusted OR 1.15, 95% CI 0.75-1.76), but the CCND1 AA genotype was associated with a significantly increased risk (adjusted OR 1.77, 95% CI 1.04-3.02) for SCCHN. Results from a trend test using a logistic regression model were statistically significant (P = 0.044). Among the cases the mean age of onset was 59.0, 56.8 and 55.5 years for the GG, GA and AA genotypes, respectively. In the stratification analysis the CCND1 AA variant genotype was associated with a >3-fold increased risk in individuals who were </=50 years old (OR 3.18, 95% CI 1.19-8.46), females (3.57, 1.26-10.0), non-smokers (3.71, 1.37-10.1) and non-alcohol users (4.76, 1.61-14.0). These results suggest that the CCND1 polymorphism is associated with early onset of SCCHN and contributes to susceptibility to SCCHN in this population.

Carcinoma, Squamous Cell↗
PubMed2001

Alcohol dehydrogenase 3 genotype is not associated with risk of squamous cell carcinoma of the oral cavity and pharynx.

Alcohol is one of the major risk factors for oral and pharyngeal cancer. The rate-limiting step in alcohol metabolism is the oxidation (activation) of ethanol to acetaldehyde by the alcohol dehydrogenases (ADHs). It has been hypothesized that individuals who are homozygous for the fast allele (ADH(1-1)(3)) are at greater risk for alcohol-related cancers. To test this hypothesis, we investigated the association between the ADH3 genotype and oral and pharyngeal cancer risk in a large racially homogeneous case-control study of 229 patients and 575 matched control subjects with frequency matching on age, sex, and smoking status. Although the smoking status was matched between cases and controls, current and former alcohol use remained a significant risk factor, compared with never use (odds ratio, 2.08; 95% confidence interval, 1.37-3.17; odds ratio, 1.97; 95% confidence interval, 1.25-3.09; and odds ratio, 1.00, respectively). The ADH1(3) allele frequency of controls was 57.4%, consistent with reports of similar racial groups (50-60%). The genotype distribution in controls was also consistent with the Hardy-Weinberg equilibrium (P = 0.51). However, the ADH1(3) allele frequency and ADH(1-1)(3) genotype frequency were not significantly different between cases and controls [55.5% versus 57.4% (P = 0.52), and 30.6% versus 31.3% (P = 0.91), respectively]. There was no association between ADH3 genotypes (ADH(1-1)(3), ADH(1-2)(3), and ADH(2-2)(3)) and risk of oral and pharyngeal cancer (odds ratios, 1.00; 0.96; 95% confidence interval, 0.68-1.37; and odds ratio, 1.23; confidence interval, 0.78-1.93, respectively). Therefore, we found no evidence that supports a main effect of ADH3 genotype or a combined effect of alcohol and ADH3 genotype on risk of cancer of the oral cavity or pharynx.

Adult↗
PubMed2001

Polymorphisms of methylene-tetrahydrofolate reductase and risk of lung cancer: a case-control study.

Previous studies have suggested that low folate intake is associated with increased risk of lung cancer. Methylene-tetrahydrofolate reductase (MTHFR) is one of the enzymes involved in folate metabolism and is thought to influence DNA methylation and nucleotide synthesis. MTHFR is highly polymorphic, and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. Therefore, we hypothesized that these variant genotypes may play a role in the etiology of lung cancer. To test this hypothesis, we investigated the association between two common MTHFR polymorphisms (C677T and A1298C) and risk of lung cancer in a non-population-based case-control study of 550 histologically confirmed lung cancer cases and 554 healthy controls. The subjects were non-Hispanic whites, and the controls were frequency-matched to the cases by age (+ or -5 years), sex, and smoking status (ever or never). Folate intake and alcohol consumption were estimated from a self-administered food-frequency questionnaire. The cases consumed significantly less folate (162 microg/day/1000 kcal) than the controls did (172 microg/day/1000 kcal; P = 0.033). However, we found no evidence for an association between the MTHFR C677T and A1298C polymorphisms and risk of lung cancer in either all of the subjects or the low folate intake subgroup; nor did we find evidence for an interaction between these two MTHFR polymorphisms and dietary folate intake or alcohol use. In multivariate logistic regression analysis, the adjusted odds ratios and 95% confidence intervals for MTHFR C677T were 1.1 (0.8-1.4) for 677CT versus 677CC wild type and 1.1 (0.7-1.7) for 677TT versus 677CC, and for MTHFR A1298C, they were 1.0 (0.8-1.3) for 1298AC versus 1298AA wild type and 1.1 (0.7-1.8) for 1298CC versus 1298AA. These results suggest that the MTHFR C677T and A1298C polymorphisms by themselves do not play an important role in the etiology of lung cancer.

Aged↗
PubMed2000

Polymorphisms of the DNA repair gene XRCC1 and risk of gastric cancer in a Chinese population.

Gastric cancer remains the leading cause of cancer death in China and other countries in eastern Asia. Studies of gastric cancer have revealed that it is a disease of complex etiology involving dietary, infectious, environmental, occupational and genetic factors. DNA repair capacity has been suggested as a genetic factor contributing to variation in susceptibility to cancer. In the present study, we described an association between 2 polymorphisms of the DNA repair gene XRCC1 and risk of gastric cancer in a Chinese population. We used a polymerase chain reaction-based assay to detect Pvu II and Nci I restriction fragment length polymorphisms (XRCC1 26304 C-->T and XRCC1 28152 G-->A, respectively) in 188 patients with gastric cancer and 166 healthy controls. The XRCC1 26304 T allele (194Trp) frequency (34.6%) was higher and the XRCC1 28152 A allele (399Gln) frequency (25.6%) was lower in healthy Chinese controls than previously reported healthy U.S. Caucasian controls (7.2% and 34.1%, respectively). Multivariate logistic regression analysis revealed that the putative high-risk genotypes XRCC1 26304 CC and XRCC1 28152 GA/AA were associated with a non-significant increased risk for gastric cancer (adjusted odds ratio [OR]=1.45, 95% confidence interval [CI]= 0.93-2.25 and OR=1.53, 95% CI= 0.98-2.39, respectively) compared with other genotypes. However, the XRCC1 26304 CC genotype was associated with a significantly increased risk for gastric cardia cancer (adjusted OR=1.86, 95% CI=1.09-3.20). Individuals with both putative high-risk genotypes (CC and GA/AA) had a significantly higher risk (adjusted OR=1.73, 95% CI=1.12-2.69), particularly for gastric cardia cancer (adjusted OR=2.18, 95% CI=1.21-3.94) than individuals with other genotypes. These findings support the hypothesis that these 2 XRCC1 variants may contribute to the risk of developing gastric cancer, particularly gastric cardia cancer.

Adult↗
PubMed2000

Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study.

BACKGROUND: Only a fraction of cigarette smokers develop lung cancer, suggesting that people differ in their susceptibility to this disease. We investigated whether differences in DNA repair capacity (DRC) for repairing tobacco carcinogen-induced DNA damage are associated with differential susceptibility to lung cancer. METHODS: From August 1, 1995, through April 30, 1999, we conducted a hospital-based, case-control study of 316 newly diagnosed lung cancer patients and 316 cancer-free control subjects matched on age, sex, and smoking status. DRC was measured in cultured lymphocytes with the use of the host-cell reactivation assay with a reporter gene damaged by a known activated tobacco carcinogen, benzo[a]pyrene diol epoxide. Statistical tests were two-sided. RESULTS: Overall, lower DRC was observed in case patients than in control subjects (P:<.001) and was associated with a greater than twofold increased risk of lung cancer. Compared with the highest DRC quartile in the control subjects and after adjustment for age, sex, pack-years of smoking, family history of cancer, and other covariates, reduced DRC was associated with increased risk of lung cancer in a dose-dependent fashion (odds ratio [OR] = 1.8 with 95% confidence interval [CI] = 1.1-3.1, OR = 2.0 with 95% CI = 1.2-3.4, and OR = 4. 3 with 95% CI = 2.6-7.2 for the second, third, and fourth quartiles, respectively; P:(trend)<.001). Case patients who were younger at diagnosis (<60 years old), female, or lighter smokers or who reported a family history of cancer exhibited the lowest DRC and the highest lung cancer risk among their subgroups, suggesting that these subgroups may be especially susceptible to lung cancer. CONCLUSION: The results provide evidence that low DRC is associated with increased risk of lung cancer. The findings from this hospital-based, case-control study should be validated in prospective studies.

Age Factors↗
PubMed2000

Epidemiologic determinants of clinically relevant prostate cancer.

While tumor volume and Gleason scores are the best available prognostic indicators for prostate cancer, contemporary predictive methods are unable to identify which men with Gleason scores of 7 have clinically insignificant tumors that will not progress and which men will develop highly aggressive prostate cancer. Our objective was to evaluate potential environmental determinants of significant prostate cancer. Subjects were patients identified from a university-based hospital and tertiary cancer center who had undergone radical prostatectomy for prostate cancer. Cases were 103 patients whose tumor volumes were </=0.5 ml. The comparison group was comprised of 225 men with larger-volume disease or with histologic evidence of extracapsular extension but without lymph node involvement. The matching criteria were ethnicity, age at diagnosis (+/-5 years), and date of diagnosis (+/-1 year). Epidemiologic data, current weight, and height were obtained. The comparison group was significantly more likely than cases to be current smokers (7.6% vs. 3.9%) and to report more pack-years smoked (30.1 vs. 23.0 years, p = 0.06). Cases tended to weigh less (85.2 vs. 87.1 kg, p = 0.1) and have lower body mass indices (26.8 vs. 27.6, p = 0.07). A similar trend was evident for weight at age 40 (79 vs. 81 kg). Cases reported a mean weight gain of 4.9 kg compared with 6. 6 kg in the comparison subjects (p = 0.05) between the ages of 25 and 40. There was no significant difference in weight gain from age 40 to current age. Cases were more likely to report having prostate cancer screening (90% vs. 80%, p = 0.02). Cases with Gleason scores </=7 (3 + 4, with 3 being the dominant grade) were younger at diagnosis than those with scores of 7 (4 + 3, with 4 being the dominant grade), were more likely (93%) to have had prostate screening, were less likely to be current smokers (4%), reported the fewest pack-years smoked (21.5 vs. 28.6 years for high-score cases and 30.1 for comparison subjects), and had the lowest average weight gain from ages 25 to 40 (4.62 vs. 6.31 kg for high-score cases). Weight gain in early adulthood and smoking thus appear to be important predictors of virulent prostate cancer. Our data also suggest that prior screening is associated with diagnosis of lower-volume and lower-score disease.

Age Factors↗
PubMed2000

Joint effect of insulin-like growth factors and mutagen sensitivity in lung cancer risk.

BACKGROUND: We hypothesize that accumulation of genetic damage is dependent on an individual's intrinsic carcinogen sensitivity and on various humoral factors (e.g., insulin-like growth factors [IGFs]) that enhance proliferation, resistance to apoptotic cell death, and clonal outgrowth of genetically damaged cells. We tested this hypothesis by determining whether proliferation potential and genetic instability are associated with the risk of lung cancer. METHODS: In a study of 183 lung cancer patients and 227 matched control subjects, we examined the joint effects of latent genetic instability (measured as mutagen sensitivity) and elevated proliferation potential (assessed by measuring IGFs) in lung cancer risk. Levels of IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in plasma were measured by use of immunoassay kits. Mutagen sensitivity was assessed by quantitating bleomycin- and benzo[a]pyrene diol epoxide (BPDE)-induced chromatid breaks in peripheral blood lymphocyte cultures. RESULTS: Although not statistically significant, the mean levels of IGF-I and the molar ratio of IGF-I/IGFBP-3 were higher in patients with advanced or poorly differentiated disease than in patients with early or well-differentiated disease. Variation in IGFs was not associated with any specific histologic type or tumor stage. High levels of IGF-I and enhanced mutagen sensitivity were individually associated with increased risk of lung cancer: odds ratio (OR) of 2.13 (95% confidence interval [CI] = 1.20-3.78) for IGF-I, 2.50 (95% CI = 1. 49-4.20) for bleomycin sensitivity, and 2.95 (95% CI = 1.72-5.06) for BPDE sensitivity. The OR was statistically significantly elevated to 8.88 for both higher IGF-I and bleomycin sensitivity (95% CI = 3.67-21.50) and to 13.53 for higher IGF-I and BPDE sensitivity combined (95% CI = 4.48-40.89). With all three risk factors considered together, the OR was 17.09 (95% CI = 4.16-70.27). High levels of IGFBP-3 alone were associated with reduced lung cancer risk: OR = 0.59 (95% CI = 0.33-1.05). CONCLUSIONS: Our data suggest that individuals with genetic instability and higher proliferation potential are at enhanced risk for lung cancer.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2000

Adenocarcinoma of the lung in young patients: the M. D. Anderson experience.

BACKGROUND: Surveillance, Epidemiology, and End Results (SEER) data for the years 1973-1992 documented that patients age < 50 years presented with more advanced disease. Because of the increase in the incidence rate of lung adenocarcinoma in the past few decades and the presentation of more advanced disease in young patients, this study was performed to determine whether differences in survival exist between younger and older patients with this disease. METHODS: The authors reviewed the experience of the University of Texas M. D. Anderson Cancer Center between 1985-1994, encompassing 157 patients age < 40 years of 4097 patients registered with adenocarcinoma of the lung. For comparison, 157 patients age > 50 years with lung adenocarcinoma were selected; these patients were matched for gender, stage of disease at presentation, and definitive therapy modality to assess survival differences more accurately. Data regarding exposure to second-hand smoke were not collected secondary to lack of documentation in the charts reviewed. RESULTS: There were no significant differences between the 2 groups with regard to the overall survival rate (P = 0.34) or time to progression (P = 0.43). Smoking status (current vs. former vs. never-smoker) was not found to be predictive of survival in either the younger group (P = 0.51) or the older group (P = 0.92). CONCLUSIONS: The data from the current study indicate that overall survival and disease free survival rates were not significantly different in these two groups. Thus, the younger patient population should be treated similarly to the older patient population. However, a surprisingly high percentage of younger patients were female (45%) and had never smoked (27%), suggesting that risk factors other than active smoking may be involved in lung carcinogenesis in these patients.

Adenocarcinoma↗
PubMed2000

Analysis of aromatic DNA adducts and 7,8-dihydro-8-oxo- 2'-deoxyguanosine in lymphocyte DNA from a case-control study of lung cancer involving minority populations.

The purpose of this study was to examine the level of smoking-related aromatic DNA adducts and oxidative DNA damage in current smokers from a lung cancer case-control study in African Americans and Mexican Americans. In addition, mutagen sensitivity (bleomycin-induced chromatid breaks), a marker of genetic susceptibility, was assessed in these patients and correlated with the level of DNA damage. Lymphocyte DNA from cases and age-, sex-, and ethnicity-matched controls was analyzed for aromatic DNA adducts (43 cases and 47 controls) and the level of 7, 8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) was determined in 46 cases and 48 controls using (32)P-postlabeling. Overall, lung cancer cases had significantly (P < 0.05) higher levels of aromatic DNA adducts and 8-oxo-dG (mean+/-SEM; 6.03+/-1.16/10(8) nucleotides and 5.82+/-0.77/10(5) nucleotides, respectively) compared to the controls (2.80+/-0.36/10(8) nucleotides and 3.65+/-0.56/10(5) nucleotides, respectively). The case-control differences for these two biomarkers were especially evident in current smokers. Both male and female lung cancer cases had higher levels of aromatic DNA adducts compared to the corresponding controls but only in men was the difference statistically significant (P=0.002). Cases who started smoking at earliest age had highest levels of aromatic DNA adducts and 8-oxo-dG. The level of aromatic DNA adducts in lung cancer cases, but not controls, was positively correlated with bleomycin-induced chromatid breaks (P=0.011). In contrast, the level of 8-oxo-dG was not correlated with mutagen sensitivity in either cases or controls or with the level of aromatic DNA adducts. The data suggest that levels of both aromatic DNA adducts and 8-oxo-dG may be useful in predicting risk of lung cancer in these minority populations. The correlation between aromatic DNA adducts and mutagen sensitivity in lung cancer cases and the trend for higher levels of DNA damage in cancer cases who started smoking earliest are particularly interesting and merit further study.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

XPD/ERCC2 polymorphisms and risk of head and neck cancer: a case-control analysis.

DNA repair capacity is central in maintaining normal cellular functions. Variants of several DNA repair genes,including the nucleotide excision repair gene XPD, have been described recently. Because we previously reported that patients with squamous cell carcinoma of the head and neck (SCCHN) had lower DNA repair capacity than healthy controls, we hypothesized that inherited polymorphisms of XPD may contribute to genetic susceptibility to SCCHN, a tobacco-related cancer. To test this hypothesis, we conducted a hospital-based case-control study of 189 SCCHN patients and 496 cancer-free controls who were frequency-matched on age, gender and smoking status. All subjects were non-Hispanic whites. Two XPD polymorphisms (C22541A and A35931C) were typed using the restriction enzymes TfiI and PstI, respectively. Multivariate logistic regression analysis was performed to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). In the controls, the frequencies of the variant 22541A and 35931C alleles were 44.7% and 33.8%, respectively. The frequency of the 22541A homozygous genotype (22541AA) was lower in cases (15.9%) than in controls (20.4%) but was not associated with risk (adjusted OR = 0.90; 95% CI = 0.52-1. 56) for SCCHN. The frequency of the 35931C homozygous genotype (35931CC) was higher in cases (16.4%) than in controls (11.5%) and associated with a borderline increased risk (adjusted OR = 1.55; 95% CI = 0.96-2.52) for SCCHN. The risk was higher in older subjects (OR = 2.22; 95% CI = 1.03-4.80), current smokers (OR = 1.83; 95% CI = 0.79-4.27) and current drinkers (OR = 2.59; 95% CI = 1.25-5.34) in the stratification analysis. These results suggest a gene-environment interaction, but this did not reach statistical significance. The findings are limited due to the relatively small numbers in the subgroups and need to be verified by further investigations.

Adult↗
PubMed2000

Gender difference in smoking effect on chromosome sensitivity to gamma radiation in a healthy population.

In the general population, there is variation in radiosensitivity associated with cancer risk. However, data on the role of epigenetic factors in the variation of radiosensitivity are scarce. Thus we investigated the effects of smoking and age on the radiosensitivity of human lymphocytes by measuring the frequency of chromosome aberrations after in vitro exposure to gamma rays in peripheral lymphocytes from 441 healthy subjects (18-95 years old). We analyzed the frequency of both spontaneous (baseline) and in vitro gamma-ray-induced (1.5 Gy) chromatid breaks in 50 well-spread metaphases per subject. The overall mean frequencies of spontaneous and induced breaks were 0.02 and 0.45 per cell, respectively. The mean frequency of induced breaks was significantly higher in men than in women (P = 0.03) but did not differ by age or ethnicity. Donors who had ever smoked showed a small but significantly increased frequency of induced breaks (mean = 0.47) compared to nonsmokers (mean = 0.41; P = 0.005). Further stratification and multivariate analyses revealed that the smoking effect was more pronounced in men than in women. These findings support a smoking effect on radiosensitivity in a healthy population, particularly in men. Therefore, when evaluating the association between radiosensitivity and susceptibility to smoking-related cancers, the effect of smoking should be taken into account.

Adult↗
PubMed2000

Gamma-radiation-induced single cell DNA damage as a measure of susceptibility to lung cancer: a preliminary report.

The comet assay is a sensitive and rapid method for detecting DNA single-strand and double-strand breaks and the individual cell's DNA repair profile. This pilot study was designed to determine whether the comet assay could measure inherited susceptibility to lung cancer. We applied the comet assay in the alkaline condition to test the DNA damage in gamma-irradiated and untreated cultured peripheral blood lymphocytes of 31 cases with previously untreated lung cancer and 39 controls. For each culture, 200 consecutive cells were examined and the number of cells with DNA uncoiling under electrophoresis ( ) was recorded. The comet tail length (the radius of the nucleus plus the length of the migrated DNA) at 400-fold magnification was measured for the first 50 identified comet cells. The mean number of induced comet cells was significantly higher in cases (96.0+/-45.7) than matched controls (68.9+/-35.8) (P<0.05). However, no significant difference was observed in induced comet tail length between cases and controls. When we categorized the number of comet cells by the 75th percentile value in the controls, a higher number of comet cells was associated with significantly increased risk for lung cancer [odds ratio = 4.8 (confidence intervals of 1.5, 15.2)] after adjustment for age, sex, ethnicity and smoking status. The number of gamma-irradiation-induced comet cells (r=0.499, P<0.05) and comet tail length (r=0.520, P<0.05) correlated with the results on a previously reported lung cancer susceptibility marker, bleomycin sensitivity. Also, the number of gamma-irradiation-induced comet cells correlated with the results of the benzo[alpha]pyrene diol epoxide mutagen sensitivity assay, which quantifies induced chromatid breaks (r=0.275, P<0.05). The comet assay might be a simple and inexpensive tool for detecting genetic susceptibility to lung cancer.

Adult↗
PubMed2000

Genetic variants of myeloperoxidase and lung cancer risk.

The cytochrome P450 family of enzymes is responsible for many of the initial metabolic conversions of procarcinogenic compounds in tobacco smoke to reactive metabolites. However, other enzyme-based systems such as myeloperoxidase (MPO) may also be involved in this metabolic process. MPO is a phase I metabolic enzyme that has a polymorphic region upstream of the gene that appears to reduce transcriptional activity. The polymorphic G-->A nucleotide base shift negates the binding region for the general transcription factor SP1. Thus, individuals with the variant allele may be provided with a protective effect due to decreased metabolic conversion of carcinogenic compounds in tobacco smoke. This study has investigated the hypothesis that individuals with the variant allele may be at a reduced risk for lung cancer. Our results demonstrate that the protective effects of the MPO variant allele reduced overall lung cancer risk in Caucasians by 48% (OR = 0.52, 95% CI 0.30-0.90, P = 0.02). There was a 72% protective effect (OR = 0.28, 95% CI 0.12-0.61, P < 0.05) evident in men but not in women. Additionally, in younger individuals (<61 years) there was a statistically significant 72% reduction in risk (OR = 0.28, 95% CI 0. 11-0.69, P < 0.05) but not in older individuals. A protective effect was observed for current smokers (OR = 0.24, 95% CI 0.10-0.58, P < 0. 05) but not in former smokers and those who had never smoked. These data demonstrate that there is a reduction in lung cancer risk associated with a variant allele of MPO that is evident in men, younger individuals and current smokers.

Base Sequence↗